Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and con...
Main Authors: | , , , , , , |
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Format: | Journal article |
Language: | English |
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Oxford University Press
2015
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author | Liu, K Edwards, B Lee, S Finelli, M Davies, B Davies, K Oliver, P |
author_facet | Liu, K Edwards, B Lee, S Finelli, M Davies, B Davies, K Oliver, P |
author_sort | Liu, K |
collection | OXFORD |
description | Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies. |
first_indexed | 2024-03-07T01:56:27Z |
format | Journal article |
id | oxford-uuid:9bdcf6bd-bfe5-4ce1-99a1-f362dde33c0d |
institution | University of Oxford |
language | English |
last_indexed | 2024-03-07T01:56:27Z |
publishDate | 2015 |
publisher | Oxford University Press |
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spelling | oxford-uuid:9bdcf6bd-bfe5-4ce1-99a1-f362dde33c0d2022-03-27T00:31:58ZNeuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9bdcf6bd-bfe5-4ce1-99a1-f362dde33c0dEnglishSymplectic Elements at OxfordOxford University Press2015Liu, KEdwards, BLee, SFinelli, MDavies, BDavies, KOliver, PAmyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies. |
spellingShingle | Liu, K Edwards, B Lee, S Finelli, M Davies, B Davies, K Oliver, P Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis |
title | Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis |
title_full | Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis |
title_fullStr | Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis |
title_full_unstemmed | Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis |
title_short | Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis |
title_sort | neuron specific antioxidant oxr1 extends survival of a mouse model of amyotrophic lateral sclerosis |
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